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Method for producing pitavastatin calcium

a production method and technology of pitavastatin, applied in the field of improved production methods of pitavastatin calcium, can solve the problems of high cost, insufficient production of 2 types of pitavastatin, and concern about costs, and achieve the effects of low cost, high selectivity, and high yield

Active Publication Date: 2020-06-09
API CORP (JP)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0056]The production method of the present invention enables safe production of pitavastatin calcium on an industrial scale in a high yield with high selectivity at a low cost.

Problems solved by technology

Furthermore, since n-butyllithium and phosphorus tribromide used for the reaction are expensive, the cost becomes high.
The method described in patent document 2 has an insufficient yield for industrial production.
In addition, the compound represented by the formula (17) and the compound represented by the formula (18) require multistep process for synthesis, which produces concern about the costs.

Method used

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  • Method for producing pitavastatin calcium
  • Method for producing pitavastatin calcium
  • Method for producing pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

example 1 (

Production of PT-DOXE)

[0249]

[0250]Under a nitrogen atmosphere, sodium hydride (20.8 g, purity 59.5%, 515 mmol) and THF (200 mL) were charged in a flask and cooled to 17° C. To this mixture was added dropwise a solution of DHAB (53.9 g, purity 91.9%, 247.1 mmol) in THF (200 mL) over 2 hr, and the solution after completion of the dropwise addition was stirred at 25° C. for 13 hr.

[0251]To the solution after stirring was added dropwise a solution of PT-ALD (40.0 g, 137.3 mmol) in THF (400 mL) over 4 hr, and the solution after completion of the dropwise addition was stirred at 25° C. for 1 hr. The solution after stirring was analyzed by HPLC to find that the conversion ratio to PT-DOXB was 99.2%.

[0252]To the solution after stirring were added dropwise n-heptane (200 mL) and water (400 mL) at 25° C. and partitioned. Thereafter, the organic layer was washed with 4 wt % aqueous sodium chloride solution, 10 wt % aqueous citric acid solution and 10 wt % aqueous sodium chloride solution. The o...

example 2 (

Production of PT-DOXB)

[0255]

[0256]Under a nitrogen atmosphere, sodium hydride (15.6 g, purity 59.5%, 386 mmol), THF (150 mL) and N,N-dimethylformamide (75 mL) were charged in a flask and cooled to 5° C. To this mixture was added dropwise a solution of DHAB (40.4 g, purity 91.9%, 185.4 mmol) in THF (150 mL) over 2 hr, and the mixed solution after completion of the dropwise addition was stirred at 8 to 10° C. for 14 hr.

[0257]To the mixed solution after stirring was added dropwise a solution of PT-ALD (30.0 g, 103.0 mmol) in THF (225 mL) over 3 hr, and the solution after completion of the dropwise addition was stirred at 8 to 10° C. for 6 hr. The solution after stirring was analyzed by HPLC to find that the conversion ratio to PT-DOXB was 98.5%.

[0258]To the solution after stirring were added dropwise n-heptane (150 mL) and water (150 mL) at 10° C. and partitioned. Thereafter, the organic layer was washed with 4 wt % aqueous sodium chloride solution, 10 wt % aqueous citric acid solution...

reference example 1 (

Preparation of Bacterial Cells)

[Preparation of Recombinant Escherichia coli 7M109 / pKV320CR1-GDH Co-Expressing Carbonyl Reductase (Hereinafter OCR1) and Glucose-1-Dehydrogenase (Hereinafter GDH)]

(1) Cloning of Gene

[0259]Primers ocr1_F (SEQ ID NO: 3) and ocr1_R (SEQ ID NO: 4) for amplifying full-length ocr1 gene were designed and synthesized based on the gene sequence (ocr1) encoding OCR1 (SEQ ID NO: 2 described in JP-B-4270918) derived from Ogataea minuta variant nonfermentans (Ogataea minuta var. nonfermentans) NBRC (former IFO) 1473. Then, PCR was performed according to a conventional method and using chromosome DNA of Ogataea-Minuta variant nonfermentans (Ogataea minuta var. nonfermentans) as a template to give an about 0.8 kbp DNA fragment.

[0260]Then, based on a gene sequence (hereinafter gdh (SEQ ID NO: 5)) encoding GDH (SEQ ID NO: 6), which is glucose-1-dehydrogenase encoded by a gene (GeneBank Accession No. AL009126.3) derived from Bacillus subtilis (Bacillus subtilis) wherein...

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Abstract

Production of pitavastatin calcium safely on an industrial scale with a high yield and high selectivity at low cost. A method of producing pitavastatin calcium including step (i) for acetalizing a compound represented by the formula (1) to give a compound represented by the formula (3), step (ii) for reacting a compound represented by the formula (3) with an acid to give a compound represented by the formula (4), and step (iii) for hydrolyzing a compound represented by the formula (4) and reacting same with a calcium compound.

Description

TECHNICAL FIELD[0001]The present invention relates to an improved production method of pitavastatin calcium.BACKGROUND ART[0002]Pitavastatin calcium has an activity to specifically and antagonistically inhibit HMG-CoA reductase which is a rate determining enzyme of cholesterol synthesis, and is used for the treatment of hypercholesterolemia, familial hypercholesterolemia and the like.[0003]Pitavastatin calcium has a chemical name: bis[(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate]-calcium represented by the following formula:[0004][0005]It is known that pitavastatin calcium can be produced by hydrolyzing a precursor compound thereof, 2-[(4R,6S)-6-[(E)-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]vinyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate ester represented by the following formula (16):[0006]wherein R7 is an alkyl group having a carbon number of 1-4.[0007]A compound represented by the formula (16) can be obtained by a Wittig reaction.[0008]Pat...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/47C07B61/00C12P17/12C07D215/14
CPCC12P17/12C07D215/14A61K31/47C07B61/00C07C309/04C07C303/32C07B2200/13A61P3/06A61P43/00
Inventor WATANABE, NAOYUKIIURA, TAKANOBUOOMIYA, HIDEKINAGAHAMA, MASAKI
Owner API CORP (JP)
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